Lead-Induced ERK Activation Is Mediated by GluR2 Non-containing AMPA Receptor in Cortical Neurons

Abstract

Lead is a persistent environmental pollutant and exposure to high environmental levels causes various deleterious toxicities, especially to the central nervous system (CNS). The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor that is devoid of the glutamate receptor 2 (GluR2) subunit is Ca 2 -permeable, which increases the neuronal vulnerability to excitotoxicity. We have previously reported that long-term exposure of rat cortical neurons to lead acetate induces decrease of GluR2 expression. However, it is not clarified whether lead-induced GluR2 decrease is involved in neurotoxicity. Therefore, we investigated the contribution of GluR2 non-containing AMPA receptor to lead-induced neurotoxic events. Although the expression of four AMPA receptor subunits (GluR1, GluR2, GluR3, and GluR4) was decreased by lead exposure, the decrease in GluR2 expression was remarkable among four subunits. Lead-induced neuronal cell death was rescued by three glutamate receptor antagonists, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, a non-selective AMPA receptor blocker), MK-801 (N-methyl-D-aspartate (NMDA) receptor blocker), and 1-naphthyl acetyl spermine (NAS, a specific Ca 2 -permeable AMPA receptor blocker). Lead exposure activated extracellular signal-regulated protein kinase (ERK) 1/2, which was significantly ameliorated by CNQX. In addition, lead exposure activated p38 mitogen-activated protein kinase (MAPK p38), and protein kinase C (PKC), which was partially ameliorated by CNQX. Our findings indicate that Ca 2 -permeable AMPA receptors resulting from GluR2 decrease may be involved in lead-induced neurotoxicity.

Neurotoxic Agent-Induced Injury in Neurodegenerative Disease Model: Focus on Involvement of Glutamate Receptors

“…Moreover, Pb exposure causes a decrease in the expression of AMPAR subunits (GluA1, GluA2, GluA3, and GluA4) with the observed decrease in GluA2 expression being particularly remarkable. Pb-induced neuronal cell death was rescued by three glutamate receptor antagonists: 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), MK-801, and 1-naphthyl acetyl spermine (a specific Ca 2+ -permeable AMPARs blocker) (Mußhoff et al, 1995; Neal et al, 2011; Ishida et al, 2017). …”

The role of PI3K-mediated AMPA receptor changes in post-conditioning of propofol in brain protection

“…It is now clear that there exist AMPARs without GluR2 subunits exhibiting considerable Ca 2+ permeability, but when they contain GluR2 subunits the permeability to Ca 2+ becomes very scarce [27, 29, 30]. The internalization of GluR2 subunits may lead to the influx of Ca 2+ , which may lead to nerve damage in the ischemic area [30, 31]. And the changes in the distribution of GluR2 subunits can cause activation of a caspase-dependent apoptotic pathway [24].…”

Low-Concentration Tributyltin Decreases GluR2 Expression via Nuclear Respiratory Factor-1 Inhibition

“…Western blotting was performed as previously described [ 49 ] with some modifications. Denaturing buffer (100 mM Tris-HCl, 4% SDS, 20% glycerol, 0.004% bromophenol blue, and 5% mercaptoethanol) was added to the protein extracts, and the extracts were incubated at 95 °C for 3 min.…”